New research from the University of Washington reveals that manipulating the gut flora can reduce neurodegeneration in Alzheimer's disease!

This article is the original of Translational Medicine Network, please indicate the source for reprinting

Author: Mia

There is growing evidence that the trillions of microbes that normally live in our guts, the so-called gut flora, have a profound impact
on how our bodies function.
Members of this microflora are able to produce vitamins, help us digest food, prevent the overgrowth of harmful bacteria, regulate the immune system, etc
.
A new study from Washington University School of Medicine in St.
Louis has found that the gut microbiota also plays a key role
in our brain health.

Today, researchers at Washington University School of Medicine in St.
Louis published a study
in Science titled "ApoE isoform– and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy.
" 。 The study, conducted in mice, found that gut bacteria — in part by producing compounds such as short-chain fatty acids — influence the behavior of immune cells throughout the body, including cells
in the brain that can damage brain tissue and exacerbate neurodegeneration in conditions such as Alzheimer's disease.

DOI: 10.
1126/science.
add1236

Research background

 01 

Alzheimer's disease (AD) is characterized by early deposition of amyloid β (Aβ) plaques, followed by pathological tau accumulation
.
Although Aβ is a necessary factor for the onset of AD, its own accumulation is not sufficient for neurodegeneration and cognitive decline
.
In contrast, pathological tau accumulation is strongly associated
with neurodegeneration and cognitive decline in AD and primary tau disease.
There is growing evidence that the gut flora of people with Alzheimer's disease is different from
that of healthy people.
But it's unclear whether these differences are a cause or a consequence of the disease, or both, and what effect altering the microbiota might have on the course of the disease
.

To date, animal studies have focused on how alterations in the gut microbiota affect Aβ pathology, rather than tau disease and neurodegeneration
.
In addition, recent studies have shown that apolipoprotein E (ApoE) subtypes strongly influence AD risk and modulate tau-mediated neurodegeneration, with different effects
on the gut microbiota.
Therefore, it is necessary to further study the effect of
intestinal flora on tau protein pathology and neurodegeneration.

Intestinal flora influences tau-mediated neurodegeneration

 02 

The researchers altered the gut microbiome
of mice susceptible to Alzheimer's-like brain injury and cognitive impairment.
The mice were genetically modified to express a mutated form of the human brain protein tau, which accumulates at 9 months of age and causes neuronal damage and brain atrophy
.
They also carry a variant of the human apolipoprotein E gene (APOE), a major genetic risk factor
for Alzheimer's disease.
People who carry one copy of the APOE4 gene variant are 3 to 4 times
more likely to develop the disease than those who carry the more common APOE3 variant.

The researchers separately evaluated these mice in rearing under sterile (GF) conditions and early in life with short-term antibiotic (ABX) treatment
.
When the genetically modified mice were raised under sterile conditions from birth, they did not acquire gut microbiota, and then by 40 weeks of age, their brains were much less damaged than mice with normal flora
.

When these mice were housed under normal, non-sterile conditions, they developed a normal flora
.
However, after taking a course of antibiotics at two weeks of age, the bacterial composition of their flora was permanently altered
.
For male mice, brain damage was reduced at 40 weeks of age, but there was no significant change
in neurodegeneration in female mice.
In addition, the protective effect of altered microbiota was more pronounced
in male mice carrying the APOE3 variant than in male mice carrying the high-risk APOE4 variant.

Further morphological and transcriptome analysis of astrocytes and microglia revealed manipulation of the gut flora to push glial cells into a more homeosta-like state, suggesting that gut microbiota strongly influences neuroinflammation and tau-mediated neurodegeneration
.
Microbiome and metabolite analysis showed that short-chain fatty acids (SCFAs) produced by microbes are mediators
of neuroinflammation-neurodegenerative axis.
The researchers supplemented mice with the APOE4 variant with SCFAs, which resulted in more reactive glial morphology and gene expression and an increase
in p-tau pathology.

Research significance

 03 

This study may provide important insights into how the microbiota affects tau-mediated neurodegeneration and suggest therapies that alter gut microbes may influence the onset or progression
of neurodegenerative diseases.

Dr.
David M.
Holtzman, the study's senior author, suggests that for mice genetically destined to develop neurodegenerative diseases, manipulating the microbiome before the animals begin to show signs of damage may have the potential to slow or prevent neurodegenerative diseases
.
This is equivalent to a person in late middle age who starts treatment
while his cognitive abilities are still normal but on the verge of impairment.
If treatment can be started on adult animal models of such genetic sensitization before neurodegeneration begins to become apparent and proven effective, it can be further tested
in humans.

Resources:

style="margin: 0px 0px 15px;white-space: normal;padding: 0px;box-sizing: border-box;"> style="white-space: normal;margin: 0px;padding: 0px;box-sizing: border-box;">Note: This article is intended to introduce the progress of medical research and cannot be used as a reference
for treatment options.
If you need health guidance, please go to a regular hospital
.

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